Mechanisms of Neoplastic Hybrid Cell Dissemination in Colorectal Cancer

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Project Summary Metastatic disease is the primary cause of cancer morbidity and mortality, resulting in >10 million deaths worldwide in 2020. Despite recent advances in our knowledge of metastatic tumor development, there is a critical need to understand the molecular mechanisms by which discrete subpopulations of neoplastic cells successfully enter circulation to improve strategies for monitoring and reducing metastatic disease burden. Our team discovered a unique disseminated neoplastic cell subtype characterized by co-expression of neoplastic and immune cell genotypes and phenotypes that can form from neoplastic-macrophage cell fusion. These hybrid cells are found in peripheral blood at numbers greater than other circulating tumor-derived cells (CTCs) and exhibit increased migratory and invasive potential as well as the ability to seed and expand at metastatic sites at rates greater than CTCs. However, the mechanisms by which hybrid cells do so is currently unknown. In my preliminary analyses of hybrid cell gene expression, I identified upregulated components from the Runt-related transcription factor 1 (RUNX1) pathway in hybrid cells compared to tumor cells. RUNX1 is a transcription factor that regulates hematopoietic stem cell differentiation and macrophage migration and has been shown to mediate metastatic conversion of tumor cells by facilitating epithelial-to-mesenchymal transition in colorectal cancer. In a hybrid cell, RUNX1 may integrate the functional behaviors of both macrophages and tumor cells into a single cell and facilitate their successful dissemination. Therefore, I hypothesize that disseminated subpopulations of neoplastic hybrid cells display differential RUNX1 meditated ~omics and functional expression that facilitates enhanced tumor dissemination. This project proposes to first assess the gene expression and phenotypic profiles of hybrid cells in colorectal cancer tumors and peripheral blood to identify characteristics of hybrid cells that successfully disseminate. Additionally, this project will evaluate the functional role of RUNX1 in facilitating enhanced hybrid cell migration and dissemination. Successful completion of these studies will define the molecular underpinnings of neoplastic hybrid cell migration and dissemination and will provide the basis for future exploration of this unique neoplastic subtype as a biomarker for the detection of early metastatic disease and tumor evolution. Furthermore, this application proposes a comprehensive and interdisciplinary training plan within a prominent academic medical and research institution that seamlessly integrates with the research proposal, providing essential training in systems and molecular cancer biology to support the candidates career goal of maintaining an academic translational oncology laboratory as a physician scientist.